title: Human and mouse granzyme A induce a proinflammatory cytokine response.
abstract: Granzyme A (GzmA) is considered a major proapoptotic protease. We have discovered that GzmA-induced cell death involves rapid membrane damage that depends on the synergy between micromolar concentrations of GzmA and sublytic perforin (PFN). Ironically, GzmA and GzmB, independent of their catalytic activity, both mediated this swift necrosis. Even without PFN, lower concentrations of human GzmA stimulated monocytic cells to secrete proinflammatory cytokines (interleukin-1beta [IL-1beta], TNFalpha, and IL-6) that were blocked by a caspase-1 inhibitor. Moreover, murine GzmA and GzmA(+) cytotoxic T lymphocytes (CTLs) induce IL-1beta from primary mouse macrophages, and GzmA(-/-) mice resist lipopolysaccharide-induced toxicity. Thus, the granule secretory pathway plays an unexpected role in inflammation, with GzmA acting as an endogenous modulator.
authors.affiliation: Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Metkar
authors.forename: Cheikh
authors.initials: C
authors.lastname: Menaa
authors.forename: Julian
authors.initials: J
authors.lastname: Pardo
authors.forename: Baikun
authors.initials: B
authors.lastname: Wang
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Marina
authors.initials: M
authors.lastname: Freudenberg
authors.forename: Stephen
authors.initials: S
authors.lastname: Kim
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Lianfa
authors.initials: L
authors.lastname: Shi
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D002448:Cell Adhesion; D016923:Cell Death; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D055785:Gene Knockdown Techniques; D053804:Granzymes / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D054353:Perforin / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D053804:Granzymes